Benzodiazepines are widely used drugs for their sedative, anxiolytic and anticonvulsant effects. They have high risk of abuse and dependence.

Many benzodiazepine drugs are available including alprazolam, bromazepam, clobazam, clonazepam, diazepam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam and temazepam.

Newer illicit designer benzodiazepines are frequently used recreationally. They are commonly sold as ‘Xanax’ (a brand name for alprazolam) but usually contain agents such as etizolam, clonazolam, or flubromazolam.

Overdose causes sedation, but except for alprazolam, which has higher potency, or when taken in combination with other sedatives, rarely leads to coma. Supportive care in normally or that is required until symptoms resolve.

The z-drugs, zolpidem and zopiclone, have similar effects to benzodiazepines in overdose and can be managed similarly.

Benzodiazepines bind to the benzodiazepine receptor, which modifies the gamma amino benzoic acid (GABA) chloride channel complex. Benzodiazepines enhance the effects of the inhibitory neurotransmitter GABA, thus central nervous system depression occurs. Benzodiazepines also cause muscle relaxation and are anticonvulsant.

Zolpidem is a potent agonist at GABAA receptors but only those containing the alpha1 subunit (corresponding to the benzodiazepine (BZ)1. It is this selectivity for BZ1 receptors that is thought to explain its greater potency as a sedative-hypnotic and lesser activity as a muscle relaxant and anticonvulsant.

Zopiclone is a potent agonist at binding sites that belong to the GABAA receptor-benzodiazepine receptor-chloride ion channel complex, but which are not the benzodiazepine specific sites.

Zolpidem and zopiclone cause sedation but have little muscle relaxant or anticonvulsant properties.

Predicting the clinical effect from the ingested dose of these agents can be difficult due to significant variations in a patient’s tolerance. Patients naïve to these drugs may get significant sedation with only a few tablets, whereas those who are tolerant may get minimal symptoms from much larger ingestions.

Increased effects should be expected with alprazolam, which has increased potency compared to other agents in this class and when there is co-ingestion with other sedative agents. The elderly and very young are also at increased risk.

All benzodiazepines are lipid soluble drugs that are absorbed fairly rapidly. The rate of absorption is an important variable in determining the clinical effects with more rapid rises in serum concentrations leading to greater depth of sedation. The extent of absorption of these drugs is high.

All are highly protein bound and have volumes of distributions of about 1 L/kg. They distribute well into the central nervous system.

All benzodiazepines are hepatically metabolised with renal clearance accounting for less than 5%. The half-life of these drugs varies widely and many have active metabolites.

Despite this variation those with a shorter half-life (e.g. temazepam) and those with a longer half-life (e.g. diazepam, clonazepam) have very similar spectrums of clinical toxicity. This results from development of tolerance. It is actually the development of tolerance to the benzodiazepines (during the period of high levels following overdose) that determines the recovery of consciousness rather than the clearance of the drug.

The clinical effects of benzodiazepine poisoning are due entirely to central nervous system depression.

Severe poisonings may develop hypothermia, bradycardia, and hypotension; however, this is unusual. Respiratory depression and depression of consciousness may lead to aspiration pneumonia. Deep coma is unusual. Most patients are stuporous or still responsive to painful stimuli unless they have co-ingested other sedating drugs.

There are no specific investigations for those with benzodiazepine toxicity, and those with mild toxicity may not require any investigations.

In those with more significant toxicity it may be useful to check blood glucose, renal function and electrolytes and an ECG.

Supportive care is the mainstay of management. Patients with more severe toxicity leading to compromised airway or breathing, should be intubated and ventilated.

Sedated patients should have intravenous fluids to maintain hydration and consideration of thromboprophylaxis and pressure cares.

Given the rapid onset of effects and expected positive outcome with supportive care, gastrointestinal decontamination is not suggested.

There is no role for enhanced elimination

Flumazenil is a benzodiazepine antagonist, that also reverses the effects of the z-drugs. Whilst it can be used both therapeutically and diagnostically, its use is generally discouraged, especially in those regularly using benzodiazepines.

In patients with benzodiazepine dependence, it can lead to withdrawal including seizures. It has also been shown to prevent the in-dose tolerance that is responsible for patients waking post overdose, and therefore can potentially prolong toxicity.

Use of flumazenil should only be considered in the following circumstances (assuming the patient does not have benzodiazepine dependence):

• To avoid intubation in the very old or young children
• Reversal of procedural sedation
• Where there is compromised airway or ventilation and intubation is not available

Use:
Flumazenil 0.1 – 0.2 mg intravenously (Child: 5mcg/kg max 0.2mg). Repeat every minute until desired effect. Max dose 2mg

The half-life of flumazenil (45-60min) is shorter than many benzodiazepines so re-sedation may occur. If this is the case then re-bolus the patient as per the dosing above and start an infusion at 2/3 the bolus dose needed per hour, titrate to effect (if increasing the rate, first bolus until desired clinic effect achieved and add the required bolus dose to the ongoing hourly rate).

Asymptomatic patients should be observed for at least 4 hours post ingestion for the onset of toxicity.

If flumazenil is given, then patients need observation for at least for hours post the last dose to ensure that re-sedation does not occur.

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